Extracellular deoxyribonuclease made by group A Streptococcus assists pathogenesis by enhancing evasion of the innate immune response
Extracellular deoxyribonuclease made by group A Streptococcus assists pathogenesis by enhancing evasion of the innate immune response
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DOI：
10.1073/pnas.0406641102
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发表时间：
2005-02-01
影响因子：
11.1
通讯作者：
Musser, JM
中科院分区：
文献类型：
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作者：
Sumby, P;Barbian, KD;Musser, JM
许多病原菌产生胞外DNA酶，但这种酶活性的益处尚不清楚。例如，人类细菌病原体A组链球菌（GAS）的所有菌株产生至少一种细胞外DNA酶，并且大多数菌株产生几种不同的酶。尽管研究了60年，但尚不清楚GAS产生的DNA酶是否会增强毒力。为了检验细胞外DNA酶是GAS感染正常进展所需的假设，我们产生了7个同基因突变株，其中3个染色体和原噬菌体编码的DNA酶由当代血清型M1 GAS菌株被灭活。与野生型亲本菌株相比，同基因三重突变菌株在两种侵袭性感染小鼠模型中的毒力显着降低。三重突变体菌株从皮肤注射部位清除的速度显著快于野生型菌株。突变株的优先清除与突变株和野生型菌株的差异细胞外杀伤有关，可能是通过降解中性粒细胞胞外陷阱、由染色质和颗粒蛋白组成的先天免疫结构。三重突变株在引起食蟹猴实验性咽部疾病的能力方面也显著受损。七个DNase突变株的比较分析强烈表明，原噬菌体编码的SdaD2酶是主要的DNase，有助于在这个克隆的毒力。我们的结论是，细胞外DNA酶活性的GAS有助于疾病的进展，从而解决了一个长期存在的问题，在细菌的发病机制研究。
Many pathogenic bacteria produce extracellular DNase, but the benefit of this enzymatic activity is not understood. For example, all strains of the human bacterial pathogen group A Streptococcus (GAS) produce at least one extracellular DNase, and most strains make several distinct enzymes. Despite six decades of study, it is not known whether production of DNase by GAS enhances virulence. To test the hypothesis that extracellular DNase is required for normal progression of GAS infection, we generated seven isogenic mutant strains in which the three chromosomal- and prophage-encoded DNases made by a contemporary serotype M1 GAS strain were inactivated. Compared to the wild-type parental strain, the isogenic triple-mutant strain was significantly less virulent in two mouse models of invasive infection. The triple-mutant strain was cleared from the skin injection site significantly faster than the wild-type strain. Preferential clearance of the mutant strain was related to the differential extracellular killing of the mutant and wild-type strains, possibly through degradation of neutrophil extracellular traps, innate immune structures composed of chromatin and granule proteins. The triple-mutant strain was also significantly compromised in its ability to cause experimental pharyngeal disease in cynomolgus macaques. Comparative analysis of the seven DNase mutant strains strongly suggested that the prophage-encoded SdaD2 enzyme is the major DNase that contributes to virulence in this clone. We conclude that extracellular DNase activity made by GAS contributes to disease progression, thereby resolving a long-standing question in bacterial pathogenesis research.